Medicaments containing horse chestnut extract (HCE) are usually derived from horse chestnut seeds, i.e. semen of Aesculus hippocastanus. Such medicaments have been described in pharmaceutical literature, for instance in the German physician's desk reference "Rote Liste" (1967), page 1333. Pharmaceutical products containing horse chestnut extract (HCE) have been manufactured and administered in the form of soft gelatin capsules, ointments, liquid formulations, ampuls or vials for injection, dragees or suppositories.
Many scientific investigations have been carried out in order to establish the active ingrdient in the horse chestnut extract (HCE), that is, the agent responsible for the biological effect on the venous system. These investigations have revealed that escin, a specific triterpene glycoside, is the essential agent of pharmacological action. In animal model and human pharmacological model it has been demonstrated that, after administration of the horse chestnut extract (HCE), the permeability of the capillary vessel involved in venous and edemic disorders is decreased by 22% compared with the untreated or placebo-treated control, see Paschinger, E. Wirz and E. Zwerger, Med. Welt, 32, (1981), pgs. 1954 et sequ. Studies carried out on horse chestnut administration to treat post-traumatic edema such as edemae after injuries, brain edema, thrombophlebitis or other disorders of the venous circulatory system (for instance venous insufficiency) it revealed that the quality and action of those conventional simple compositions were not satisfactory. It was recognized that the release rate of the active ingredient needed improvement because of its irregular and unreliable behaviour in the blood stream and its short lasting action. Prolonged action and regular therapeutical levels in the blood stream (when the medicament is administered in solid form) can be achieved in a number of different ways. For example, multi-layer tablets, embedded or matrix forms, molded tablets, extrusion, "mantled" tablets or so-called pellet preparations all of which after administration show more or less sustained agent release in different sections of the gastro-intestinal tract according to the specific drug designs and characteristics of the agent and ingredients as well as the particular preparation technique.
Since the early 1950s attempts were made to develop extended release products. Since then, the manufacture of pellets has been the subject of intensive research, in particular with the development of innovative formulations. Conventionally, the word "pellet" has been used to describe a variety of systematically produced geometrically defined agglomerates comprising the drug and different ingredients such as binding agents, carriers and, if necessary, specific coatings. Pelletization inter alia is an agglomeration process that converts fine powders or granules of bulk drugs and excipients into small, free-flowing, spherical or semi-spherical units which are referred to as pellets. They range in size, typically, between 500 to 1500 .mu.m, but diameters of less than 500 .mu.m can also be used. Some of the most widely used pelletization processes in the art are extrusion or spheronization methods. In addition to this process solution/suspension layering or powdered layering are also utilized.
Pellets have great importance in pharmaceutical industry for various reasons. Pelletized products not only show flexibility in dosage form, design and development, but are also utilized to improve the safety and potential of an almost ideal bioavailability of drugs. When pellets containing the active ingredient are administered in vivo in the form of suspension, capsules or disintegrating tablets, they have significant therapeutic advantages over single-unit dosage forms.
Because pellets disperse freely in the gastrointestinal tract, they maximize drug absorption, reduce peak plasma fluctuations and minimize potential side effects without notably lowering drug bioavailability.
This kind of unit dosage form also reduces variations in gastric emptying rates and overall transit times. In this way the undesirable variability of plasma profiles which are common with other conventional dosage forms such as single-unit medicaments in the form of simply compacted tablets or drage e cores, are minimized. A further advantage of pellets over the conventional single-unit dosage forms as indicated above is that high local concentrations of drugs which may inherently be irritative or anaestethic with conventional sustained release medicaments can be avoided.
Controlled release pellets are prepared either to deliver the drug at a specific site within the gastrointestinal tract or to sustain the action of drugs over an extended period of time. Another advantage of manufacturing pellets is an enormous flexibility during the development of oral dosage forms, for instance, pellets composed of different drug entities can be blended and formulated in a single dosage form. This procedure allows the combined delivery of two or more drugs that may or may not be chemically compatible, to the same or different sites within the gastro-intestinal tract. A combination of pellets of different drugs, optionally having different release rates, administered as a single dose may be delivered to the same area or optionally to different sections of the gastrointestinal tract. Furthermore, pellets have a low surface area-to-volume ratio and provide an ideal shape for the application of film coatings. It is important that pellets of reproducible weights for charging capsules can be achieved in order to conform to the FDA's Good Manufacturing Practice (GMP) Regulations.
As alternatives to the above pelletization processes are other conventional methods including conventional such as globulation, balling or compression.
As a first pelletization step, a conventional granulation process is followed by globulation or spheronization is used. However, various problems arise depending on the specific drugs to be pelletized. In particular plant extracts tend to agglomerate before processing usually because of their hygroscopicity. Further problems may arise in coating the pellets to achieve sustained release and to obtain reproducible release rates. Matrix pellets may be used instead of coated pellets. Matrix pellets have the drug embedded in a matrix of lipid substance or polymers where one or more bioactive agents is set free within the gastrointestinal tract by erosion. In contrast to this erosion form, the active ingredient is released across the fine pored water-insoluble, permeable coating membrane of the above said coated pellet, the coating, for instance, consisting of polymers built up by unsaturated organic acid monomer units.
This form shows a mechanism which is substantially uneffected by pH, ion concentration or enzyme activity in the gastro-intestinal tract. Coated pellets having this pH-independent release mechanism are called diffusion pellets which following their uptake are distributed within the gastro-intestinal tract and gradually release the respective agent through the micropores of a suitable polymeric coating.
Among the above pharmaceutical compositions containing horse chestnut extract (HCE) the pellet form was chosen to study its applicability for developing a medicament on the basis of that plant extract having an improved quality, in particular superior drug safety and bioavailability. It has been demonstrated that the choice for an pH-independent agent release system, that is a coated pellet form, causes a series of further problems and drawbacks. Investigations carried out have shown that the type and composition of the horse chestnut extract (HCE) and additives used to form and spheronize the pellets, presents problems to the pellet surface consistency, that is its uniformity, for instance concerning its ideal ball or globule shape.
The pellet processing usually leads to irregular, uneven and coarse surfaces and a broad mean grain distribution of the pellets to be manufactured. It also leads to mechanical problems such as blocking of machine parts or undesired agglomerations during pelletizing. Conventional horse chestnut extracts (HCE) obtained by drying the extracted seed material over heated drums or under reduced pressure in heated boxes are especially prone to cause considerable mechanical pelletizing problems which can result in blocked apparatus. This results in lost batches and unproductive working hours. Those conventional pelletizing processes employing common extract materials have been found to be very expensive and uneconomical. Furthermore, the drug safety was not found to be satisfactory and the desired release rates were not obtained.
Studies have revealed that there are many problems associated with irregular pellet form and surface which lead to unforseeable disadvantageous properties of the finished pellets. It has been found that the problems also influence the release rates so that a substantial quantity of successfully pelletized material made of conventionally dried seed extract is rejected because of batches that do not conform to the necessary drug quality standards. This is the case for the coated sustained release pellets made of conventionally prepared seed extract having an irregular shape. These drawbacks lead, inter alia, to problems in encapsulating the pellets containing the active ingredient or principle by causing undesired dosage deviations. Furthermore it has been recognized that these problems impair the drug quality and safety in addition to economical losses, undue energy consumption, machine down-time (in which machines are out of action for long periods after blockage and during cleaning) and additional wage costs etc.